Alzheimer's disease (AD), a neurodegenerative disease that is the most common cause of dementia in the elderly and poses immense burdens on society, is characterized neuropathologically by -amyloid plaques and tau neurofibrillary tangles. A recent series of papers has revealed that AD-like neuropathology can first be detected in the locus coeruleus (LC), a brainstem noradrenergic nucleus implicated in learning and memory that degenerates early in AD. Furthermore, LC lesions exacerbate, while pro-noradrenergic treatments ameliorate, AD-like neuropathology and cognitive deficits in transgenic mouse models of the disease. However, these studies have been limited by reliance on mouse AD models that do not recapitulate critical aspects of the disease such as bona fide tau tangles and neuronal loss. In addition, current noradrenergic manipulations cannot distinguish between the two distinct modes of LC firing, tonic and phasic, which have very different effects on cognition and neurotransmitter release. To overcome these limitations, we will use optogenetics to drive tonic or phasic LC activity in the TgF344-AD transgenic rat that manifests all critical neuropathological and cognitive hallmarks of AD. Completion of these studies will identify the most beneficial firing modes and neuromodulators responsible for the pro-cognitive and neuroprotective properties of the LC, thus laying the groundwork for the design of LC-based therapies for the treatment of AD.